Predicting the 28-day prognosis of acute-on-chronic liver failure patients based on machine learning.

BACKGROUND: We aimed to establish a prognostic predictive model based on machine learning (ML) methods to predict the 28-day mortality of acute-on-chronic liver failure (ACLF) patients, and to evaluate treatment effectiveness. METHODS: ACLF patients from six tertiary hospitals were included for analysis. Features for ML models' development were selected by LASSO regression. Models' performance was evaluated by area under the curve (AUC) and accuracy. Shapley additive explanation was used to explain the ML model. RESULTS: Of the 736 included patients, 587 were assigned to a training set and 149 to an external validation set. Features selected included age, hepatic encephalopathy, total bilirubin, PTA, and creatinine. The eXtreme Gradient Boosting (XGB) model outperformed other ML models in the prognostic prediction of ACLF patients, with the highest AUC and accuracy. Delong's test demonstrated that the XGB model outperformed Child-Pugh score, MELD score, CLIF-SOFA, CLIF-C OF, and CLIF-C ACLF. Sequential assessments at baseline, day 3, day 7, and day 14 improved the predictive performance of the XGB-ML model and can help clinicians evaluate the effectiveness of medical treatment. CONCLUSIONS: We established an XGB-ML model to predict the 28-day mortality of ACLF patients as well as to evaluate the treatment effectiveness.

Impact of Onset Time, Number, Type, and Sequence of Extrahepatic Organ Failure on Prognosis of Acute-on-chronic Liver Failure.

Background and Aims: The impact of the characteristics of extrahepatic organ failure (EHOF) including the onset time, number, type, and sequence on the prognosis of acute-on-chronic liver failure (ACLF) patients remains unknown. This study aimed to identify the association between the characteristics of EHOF and the prognosis of ACLF patients. Methods: ACLF subjects enrolled at six hospitals in China were included in the analysis. The risk of mortality based on the characteristics of EHOF was evaluated. Survival of study groups was compared by Kaplan-Meier analysis and log-rank tests. Results: A total of 736 patients with ACLF were included. EHOF was observed in 402 patients (54.6%), of which 295 (73.4%) developed single EHOF (SEHOF) and 107 (26.6%) developed multiple EHOF (MEHOF). The most commonly observed EHOF was coagulation failure (47.0%), followed by renal (13.0%), brain (4.9%), respiratory (4.3%), and circulatory (2.3%) failure. Survival analysis found that MEHOF or SEHOF patients with brain failure had a worse prognosis. However, no significant outcome was found in the analysis of the effect of onset time and sequence of failed organs on prognosis. Patients were further divided into three risk subgroups by the EHOF characteristics. Kaplan-Meier analysis showed that risk stratification resulted in the differentiation of patients with different risks of mortality both in the training and validation cohorts. Conclusions: The mortality of ACLF patients was determined by the number and type, but not the onset time and sequence of EHOF. Risk stratification applicable to clinical practice was established.

TEDC2 plays an oncogenic role and serves as a therapeutic target of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies and tends to have a poor prognosis due to its insidious onset, difficulty in early diagnosis, and limited treatment options. Tubulin epsilon and delta complex 2 (TEDC2), also known as C16orf59, is implicated in maintaining centriole stability, but the involvement of TEDC2 in HCC remains unknown. This study aimed to investigate the expression profile and potential mechanisms of TEDC2 in HCC. METHODS: Multiple RNA sequencing datasets were screened for differentially expressed genes in HCC, and the prognosis-related gene, TEDC2, was further screened as a target gene in this study. The expression of TEDC2 in public datasets and clinical specimens was analyzed, and the involvement of TEDC2 in HCC was investigated by bioinformatic analysis and in vitro experiments. RESULTS: TEDC2 levels were elevated in HCC compared to healthy livers. Overexpression of TEDC2 was positively correlated with pathologic stage and histologic grade. In addition, TEDC2 was found to be an independent prognostic predictor. An excellent prognostic model of HCC was successfully constructed with TEDC2 in combination with the TNM stage. Bioinformatic analysis revealed that overexpression of TEDC2 might be associated with impaired tumor immunity in HCC, as evidenced by increased infiltration of T helper 2 (Th2) cells and reduced infiltration of cytotoxic cells. Further studies showed that TP53 mutations regulated TEDC2 expression, and TEDC2 was significantly associated with drug sensitivity. Moreover, overexpression of TEDC2 promoted cell metastasis and proliferation in vitro. CONCLUSION: These findings initially suggested a crucial effect of TEDC2 overexpression on HCC tumor progression, suggesting its potential as a novel prognostic and therapeutic target in HCC.

The mediating effect of psychological resilience on empathy and professional identity of Chinese nursing students: A structural equation model analysis.

BACKGROUND: Previous studies have shown that empathy has a positive impact on the professional identity of nursing students. And developing psychological resilience can improve the professional identity of nursing students. However, studies investigating the mechanism of the relationship between empathy and psychological resilience on professional identity remain few. PURPOSE: Among Chinese nursing students, we sought to determine whether psychological resilience mediates the association between empathy and professional identity. METHODS: A total of 495 undergraduate and postgraduate nursing students in a medical university nursing college in Hefei were investigated by demographic data questionnaire, nursing students' empathy scale, nursing students' professional identity questionnaire, and psychological resilience questionnaire. Structural equation modeling was used to analyze the mediating effect of psychological resilience between empathy and the professional identity of nursing students. RESULTS: The total score of professional identity of nursing students was 57.07 ± 10.38. Psychological resilience (r = 0.316, P < 0.01) and professional identity (r = 0.313, P < 0.01) both had positive correlations with empathy, respectively. Additionally, there was a strong correlation between psychological resilience and professional identity (r = 0.488, P < 0.01). Empathy had an indirect effect on professional identity through psychological resilience, with a direct effect of 0.256 and an indirect effect of 0.145, and the indirect effect accounted for 36.16 % of the total effect. CONCLUSION: Nursing educators should pay attention to the cultivation of empathy ability and psychological resilience to enhance nursing students' professional identity.

Controlled Synthesis of Diphosphine-Protected Gold Cluster Cations Using Magnetron Sputtering Method.

We demonstrated, for the first time, atomically precise synthesis of gold cluster cations by magnetron sputtering of a gold target onto a polyethylene glycol (PEG) solution of 1,3-bis(diphenylphosphino)propane (Ph2PCH2CH2CH2PPh2, dppp). UV-vis absorption spectroscopy and electrospray ionization mass spectrometry revealed the formation of cationic species, such as [Au(dppp)n]+ (n = 1, 2), [Au2(dppp)n]2+ (n = 3, 4), [Au6(dppp)n]2+ (n = 3, 4), and [Au11(dppp)5]3+. The formation of [Au(dppp)2]+ was ascribed to ionization of Au(dppp)2 by the reaction with PEG, based on its low ionization energy, theoretically predicted, mass spectrometric detection of deprotonated anions of PEG. We proposed that [Au(dppp)2]+ cations thus formed are involved as key components in the formation of the cluster cations.

Sirt3-mediated mitochondrial dysfunction is involved in fluoride-induced cognitive deficits.

Excessive fluoride is capable of inducing cognitive deficits, but the mechanisms remain elusive. This study aimed to investigate the effects and underlying mechanisms of fluoride on mitochondrial dysfunction and neurobiological alterations, as well as cognitive impairment. C57BL/6 mice were orally administered 25, 50, and 100 mg/L NaF for 90 days. Cultured human neuroblastoma SH-SY5Y cells were exposed to NaF (110 mg/L) for 24 h in the presence or absence of Sirt3 overexpression. The results demonstrated that chronic exposure to high fluoride induced cognitive deficits and neural/synaptic injury in mice. Fluoride reduced mitochondrial antioxidant enzyme activities and elevated SOD2 acetylation by downregulating Sirt3 expression in the brains of mice and NaF-treated SH-SY5Y cells. Moreover, fluoride lowered mtDNA transcription and induced mitochondrial dysfunction along with increased FoxO3A acetylation in the brains of mice and NaF-treated SH-SY5Y cells. Subsequent experiments revealed that overexpression of Sirt3 significantly attenuated the adverse effects of fluoride on radical scavenging capabilities and mtDNA transcription, as well as mitochondrial function in SH-SY5Y cells. These results suggest that chronic long-term fluoride exposure evokes neural/synaptic injury and cognitive impairment through mitochondrial dysfunction and its associated oxidative stress, which is, at least partly, mediated by Sirt3 inhibition in the mouse brain.

C-phycocyanin Mitigates Cognitive Impairment in Doxorubicin-Induced Chemobrain: Impact on Neuroinflammation, Oxidative Stress, and Brain Mitochondrial and Synaptic Alterations.

Chemotherapy-induced cognitive impairment (CICI) is a common detrimental effect of cancer treatment, occurring in up to 75% of cancer patients. The widely utilized chemotherapeutic agent doxorubicin (DOX) has been implicated in cognitive decline, mostly via cytokine-induced neuroinflammatory and oxidative and mitochondrial damage to brain tissues. C-phycocyanin (CP) has previously been shown to have potent anti-inflammatory, antioxidant, and mitochondrial protective properties. Therefore, this present study was aimed to investigate the neuroprotective effects of CP against DOX-elicited cognitive impairment and explore the underlying mechanisms. CP treatment (50 mg/kg) significantly improved behavioral deficits in DOX-treated mice. Furthermore, CP suppressed DOX-induced neuroinflammation and oxidative stress, mitigated mitochondrial abnormalities, rescued dendritic spine loss, and increased synaptic density in the hippocampus of DOX-treated mice. Our results suggested that CP improves established DOX-induced cognitive deficits, which could be explained at least partly by inhibition of neuroinflammatory and oxidant stress and attenuation of mitochondrial and synaptic dysfunction.

Original endomorphin-1 analogues exhibit good analgesic effects.

A new class of endomorphin-1 analogues was synthesized by combining successful chemical modifications including N-terminal guanidino modification, Phe4 was chlorinated, D-Ala-Gly Substituted L-Pro2. Their bioactivities were measured by radioligand binding assay, metabolic stability and the tail-flick test. In radioligand binding assays, analogue GAGPC (Nα-Amidino-Tyr-D-Ala-Gly-Trp-p-Cl-Phe-NH2), shown a µ-opioid receptor affinity about 1.42-fold higher and a 2.51-fold higher δ-opioid receptor affinity than EM-1. In the metabolic stability assays, GAGPC had the longest half-lives which was 284min and 53-fold higher than that of EM-1. In the tail-flick test in mice, GAGPC chloride modification increases the lipid content of the drug, thus increases the permeability of the blood brain barrier, and has a higher analgesic activity. It might be of importance in potential application as drug candidates as analgesic.

[5'-flanking regulatory sequence methylation of the Boule gene in the testis tissue of infertile men with Sertoli cell-only syndrome].

OBJECTIVE: To investigate the 5'-flanking regulatory sequence methylation status of the Boule gene in the testis tissue of infertile men with Sertoli cell-only syndrome (SCOS). METHODS: We collected biopsy samples of the testis tissue from 12 men with obstructive azoospermia (the control group) and 15 cases of SCOS, all without varicocele, cryptorchidism, or infectious disease. We extracted genomic DNA from the testis tissue of the SCOS patients, analyzed the characteristics of the 5'-flanking regulatory sequence of the Boule gene using the bioinformatics method, and detected the methylation status of the Boule gene by sodium bisulfite sequencing. RESULTS: A CpG island was observed in the 5'-flanking regulation region of the Boule gene. The methylation level of the Boule gene was remarkably higher in the SCOS group than in the obstructive azoospermia controls (61.4% vs 21.7%, P<0.01), with significant differences in the methylation levels of 14 CpG sites, namely, －58 bp, －50 bp, －48 bp, －38 bp, －28 bp, －24 bp, －20 bp, －15 bp, －1 bp, +5 bp, +8 bp, +15 bp, +29 bp, and +58 bp. CONCLUSIONS: The methylation level of the Boule gene is significantly higher in the SCOS patients than in the obstructive azoospermia males, which suggests that the changes in Boule methylation may be associated with spermatogenic dysfunction.

hPEBP4 as a predictive marker for the pathological response of rectal cancer to preoperative radiotherapy.

PURPOSE: The ability to predict tumor sensitivity toward radiotherapy is important in the personalized application of preoperative radiotherapy for patients with rectal cancer. The aim of the present study was to test the human phosphatidylethanolamine-binding protein 4 (hPEBP4) as a predictive marker of tumor response to preoperative radiotherapy in patients with rectal cancer. METHOD: A retrospective analysis was conducted, consisting of 86 patients with locally advanced rectal cancer who underwent short-course preoperative radiotherapy (20 Gy in five fractions for 1 week) followed by a radical resection. Both pretreatment biopsy specimens and resected primary tumor tissue were collected. Immunohistochemistry and tumor regression grading system were used to evaluate the expression of hPEBP4 in the pretreatment biopsy specimens and the response of rectal cancer to radiotherapy, respectively. Expression of hPEBP4 was correlated with tumor regression in the resected specimen and the clinical outcome of the patients as well. RESULTS: We found that high expression of hPEBP4 was associated with radioresistance in both univariate and multivariate analyses, and patients with a high hPEBP4 expression had a poorer progression-free survival than those with low hPEBP4 expression. CONCLUSION: Our study revealed the independent predictive values of hPEBP4 in response of rectal cancer to preoperative radiotherapy, which suggests that upregulating hPEBP4 might be a potential mechanism by which rectal cancer cells avoid the destructive effects of radiotherapy.

Involvement of transforming growth factor-beta in regulation of calcium transients in diabetic vascular smooth muscle cells.

Altered calcium [Ca2+] transients of vascular smooth muscle cells to vasoconstrictors may contribute to altered regulation of blood flow in diabetes. We postulated that diabetes-induced transforming growth factor (TGF)-beta production contributes to impaired ANG II response of vascular smooth muscle cells in macrovessels and microvessels. Aortic vascular smooth muscle cells isolated from diabetic rats exhibited markedly impaired ANG II-induced cytosolic calcium [Ca2+] signal that was completely restored by pretreatment with anti-TGF-beta antibodies. Similar findings were noted in microvascular smooth muscle cells isolated from preglomerular vessels and cultured in high glucose. The impact of diabetes on [Ca2+] transients was replicated by addition of TGF-beta1 and -beta2 isoforms to aortic smooth muscle cells in culture and diabetic cells had enhanced production of TGF-beta2. In the in vivo condition, TGF-beta1 was increased in diabetic glomeruli, whereas TGF-beta2 was increased in diabetic aorta. The characteristic increase in glomerular filtration surface area found in diabetic rats was prevented by treatment with anti-TGF-beta antibodies, and impaired ANG II-induced aortic ring contraction in diabetic rats was completely restored by anti-TGF-beta antibodies. Impaired vascular dysfunction may be partly due to decreased inositol 1,4,5-trisphosphate receptor (IP3R), as reduced type I IP3R expression was found in diabetic aorta and restored by anti-TGF-beta antibodies. We conclude that TGF-beta plays an important role in the vascular dysfunction of early diabetes by inhibiting calcium transients in vascular smooth muscle cells.

TGF-beta-induced Ca(2+) influx involves the type III IP(3) receptor and regulates actin cytoskeleton.

Ca(2+) influx has been postulated to modulate the signaling pathway of transforming growth factor-beta (TGF-beta); however, the underlying mechanism and functional significance of TGF-beta-induced stimulation of Ca(2+) influx are unclear. We show here that TGF-beta stimulates Ca(2+) influx in mesangial cells without Ca(2+) release. The influx of Ca(2+) is prevented by pharmacological inhibitors of inositol 1,4,5-trisphosphate receptors (IP(3)R) as well as specific antibodies to type III IP(3)R (IP(3)RIII) but not to type I IP(3)R (IP(3)RI). TGF-beta enhances plasma membrane localization of IP(3)RIII, whereas the sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase (SERCA) preferentially translocates to the nucleus. Untreated mesangial cells exhibit actin filamentous protrusions on the cell surface, and treatment with TGF-beta dramatically reduces this pattern. The alterations in the actin cytoskeleton by TGF-beta are dependent on TGF-beta-induced Ca(2+) influx. These studies identify a novel pathway by which TGF-beta regulates Ca(2+) influx and induces cytoskeletal alterations.